There is at present no accepted molecular mechanism to explain how disease processes in vivo could be caused by exposure to low levels of nonionizing, nonthermogenic electromagnetic fields (EMF). Based on our previous work with bone cells and other cell types, we have hypothesized that EMF interacts with cells primarily at the level of membrane signal transduction mechanisms, and we have shown that G protein linked receptors are modulated by exposure to EMF as low as I gauss. In recent experiments we have demonstrated a transient activation, followed by a strong downregulation, of protein kinase C (PKC) activity in bone cells exposed to a 1 gauss, 60 Hz sinusoidally varying magnetic field. This is the strongest and most immediate effect yet observed of low energy EMF on bone cells in culture. Other experiments indicate that the same field desensitizes adenylyl cyclase activation by parathyroid hormone and beta- adrenergic receptors in several cell types, effects which could be secondary to activation or downregulation of PKC. PKC is also the site of action of tumor promoting agents such as the phorbol esters. We propose to examine in detail the biochemical mechanisms associated with activation and downregulation of PKC by EMF in mammalian target cells, and determine what role this modulation of PKC activity may have in other effects of EMF on signal transduction. We will expose osteoblast cultures (normal and neoplastic), HL-60 leukemia cells and pineal cells to low energy 60 Hz sinusoidally varying EMF between 10 milligauss and 10 gauss (initial experiments will be done at 1 gauss). We will determine the activity of G protein linked membrane receptors in the cells by measuring their responses to appropriate hormones in terms of PKC activation and downregulation, inositol phospholipid turnover, Ca++ transport and adenylyl cyclase activation. We will also study in detail the regulation of PKC in terms of EMF effects on sensitivity to activating agents (including tumor promoting agents) and inhibitors, isozyme profiles, degradation rates and modulation by phospholipase C. We also will determine whether the observed effects on PKC are reflected by changes in other pathways and/or expression of genes normally regulated by PKC. These studies will help to establish a mechanistic framework within which the possible effects of EMF on health can be understood at the molecular level.